Increased prevalence and severity of both substance and behavioral addictions are among the most harmful consequences of the COVID-19 outbreak. To determine the sociodemographic characteristics, COVID-19-related stressors, and stress, anxiety, and depression symptoms that may predict the use and changes in the use of psychoactive substances (PS) during the first three COVID-19 waves in Croatia. The cross-sectional online survey included 1,118 adult participants (220 men and 898 women; mean age: 35.1 SD = 12.3 years; age range: 18-78) from general adult population. Sociodemographic data were collected, and ad-hoc developed questionnaires on COVID-19-related stressors, PS use before and during the pandemic, CAGE Alcohol Questionnaire, Impact of Event Scale, and Hospital Anxiety Depression Scale were applied. The PS use increased in 31% of participants. The use of tobacco, caffeine, alcohol, cannabinoids, and anxiolytics showed the greatest increase in the last year (tobacco 7.1%; caffeine 5.8%; alcohol 6.4%; cannabinoids 2.5%; and anxiolytics 3.9%). Alcohol consumption during the pandemic increased in 16.8% of participants who consumed alcohol before the pandemic, with 4.5% of them reporting problematic alcohol use (PAU). The tested model demonstrated relatively good model-data fit and significantly predicted 11.8% increase in the use of PS and 9.8% of PAU. Being married or in a relationship and severe anxiety and depression symptoms predicted increased use of PS and PAU, while higher education level and ever being diagnosed with COVID-19 predicted only increased use of PS.